目的 通过调节纳米骨架载药系统（NDDS）中载体类型和比例实现对缬沙坦体外溶出和体内生物利用度的调控。方法 以缬沙坦作为模型药物，分别选取酸性敏感材料Eudragit E100（E100）、碱性敏感材料Eudragit L100-55（L100-55）作为载体材料，介孔二氧化硅Sylysia 350（S350）、Aerosil 200（A200）作为纳米骨架，通过调节载体和骨架材料的类型和比例筛选出具有pH 1.2、6.8敏感释放行为的纳米骨架载体处方，考察缬沙坦在pH 1.2、6.8环境中释放和在大鼠体内的药动学行为特征。结果 筛选的pH 1.2敏感释放缬沙坦NDDS处方缬沙坦、S350、E100比例为1∶3∶1，pH 6.8敏感释放缬沙坦NDDS处方为缬沙坦、A200、L100-55比例为1∶1∶3。pH 6.8敏感释放处方可调控缬沙坦在肠道pH 6.8条件下特异性溶出；pH 1.2敏感释放处方在保持缬沙坦在pH 6.8高溶出特性的同时可特异性地提高胃部酸性条件下的药物释放。pH 1.2、6.8敏感释放缬沙坦NDDS均一定程度上改善了缬沙坦的生物利用度，其中pH 6.8敏感释放缬沙坦NDDS提高生物利用度的幅度更高，血药浓度变化比较平缓。结论 NDDS可以调控缬沙坦的体外溶出和生物利用度，有望应用于pH值敏感性难溶药物的递送。

Objective To control in vitro dissolution and in vivo bioavailability of valsartan (Val) by adjusting the carrier type and ratio in nano-matrix drug delivery system (NDDS). Methods Valsartan was used as the model drug, acid-sensitive material Eudragit E100 (E100) and alkali-sensitive material Eudragit L100-55 were selected as carrier materials, and mesoporous silica Sylysia 350 (S350) and Aerosil 200 were used as nano-framework. The nano-framework carrier formulations with pH 1.2 and 6.8 sensitive release behavior were screened out in different proportions, and the release of valsartan in pH 1.2 and 6.8 environment and the pharmacokinetic behavior characteristics in rats were investigated. Results The ratio of Val, S350, and E100 in the NDDS formulation of pH 1.2 sensitive release valsartan was 1:3:1, and the ratio of Val, A200, and L100-55 in the NDDS formulation of pH 6.8 sensitive release valsartan was 1:1:3. The pH 6.8 sensitive release formulation can control the specific dissolution of valsartan at pH 6.8 in the intestinal tract, and the pH 1.2 sensitive release formulation can specifically improve the dissolution rate of valsartan under the acidic gastric condition while maintaining the high dissolution characteristics of valsartan release at pH 6.8. Both pH 1.2 and 6.8 sensitive release valsartan NDDS improved the bioavailability of valsartan to a certain extent. Among them, pH 6.8 sensitive release valsartan NDDS improved the bioavailability more, and the blood concentration changed more gently. Conclusion NDDS can regulate the in vitro dissolution and bioavailability of valsartan, which is expected to be applied to the delivery of pH-sensitive insoluble drugs.

R927.1

国家重大科学研究计划项目(2015CB932100)